Abstract The rewarding aspects of food is an important driving force mediating the decisions to seek food, including the overeating observed in many cases of obesity. In recent years, studies suggest that a lower functional dopamine system is associated with obesity. Our preliminary data suggest that the dopamine system, the central component of reward pathways, is especially important when food seeking-related energy cost is an important factor in decision to seek food. We hypothesize that individuals with lower dopaminergic function will shift their feeding behavior toward overeating when food is relatively easy to obtain. Our hypothesis would predict that lower dopaminergic function or leptin signaling deficiency in dopamine neurons can in deed cause obesity but only in an environment with abundance of low-cost and energy-rich foods, typical of the modern society. The proposed experiments are designed to test the causal link between hypo-dopaminergic activity and obesity and the hypothesized mechanisms. We will first establish whether hypo-dopaminergic activity and the hypothesized mechanisms contribute to obesity in leptin deficient mice. We will then establish whether hypo-dopaminergic activity and the hypothesized mechanisms contribute to diet-induced obesity. Lastly, we will examine gene-environment interactions in food seeking behavior and obesity. We will test whether dopamine D2 receptor deficient mice will be more susceptible and hyperdopaminergic mice will be more resistant to diet induced obesity in an environment with abundance of energy-rich foods.